Ontology highlight
ABSTRACT:
PROVIDER: PRJNA530665 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8840730_1.fastq.gz | Fastqsanger.gz | |||
| SRR8840730_2.fastq.gz | Fastqsanger.gz | |||
| SRR8840731_1.fastq.gz | Fastqsanger.gz | |||
| SRR8840731_2.fastq.gz | Fastqsanger.gz | |||
| SRR8840732_1.fastq.gz | Fastqsanger.gz |
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Project description:Acquired resistance of temozolomide (TMZ) is one of the major obstacle of glioblastoma clinical treatment and the mechanism of TMZ resistance is still not very clear. In the presented research we show that deletion of rs16906252-associated MGMT enhancer in MGMT negative glioma cells induced increase sensitivity to temozolomide and combination of RNA-seq and Capture HiC identified several long-range target genes of rs16906252-associated MGMT enhancer. In addition, HiC data shows alterations of chromatin structures in glioma cells survived from high-dosage TMZ treatment and changes of TADs influence rs16906252-associated MGMT enhancer’s long-range regulations of target genes. Our study suggests rs16906252-associated MGMT enhancer regulates glioma cells’ TMZ sensitivity by long-range regulations of several target genes, which is a novel mechanism of regulation of TMZ sensitivity in glioma cells.
2020-04-02 | GSE129476 | GEO
Project description:Temozolomide (TMZ) has been used for the treatment of glioblastoma (GBM) since last decade, but its treatment benefits are limited by acquired resistance, a process that remains incompletely understood. Here we report that a novel enhancer, located between the promoters of Ki67 and O6-methylguanine-DNA-methyltransferase (MGMT) genes, is activated in TMZ-resistant patient-derived xenograft (PDX) lines as well as in recurrent tumor samples. Activation of the enhancer correlates with increased MGMT expression, a major known mechanism for TMZ resistance. We show that forced activation of the enhancer in cell lines with low MGMT expression results in elevated MGMT expression. Deletion of this enhancer in cell lines with high MGMT expression leads to reduced levels of MGMT and Ki67, increased TMZ sensitivity and impaired proliferation. Together, these studies uncover a novel mechanism that regulates MGMT expression, confers TMZ resistance and potentially regulates tumor proliferation.
2018-07-13 | GSE113816 | GEO
Project description:Sensitivity to temozolomide (TMZ) is restricted to a subset of glioblastoma patients, with the major determinant of resistance a lack of promoter methylation of the gene encoding the DNA methyltransferase MGMT, although other mechanisms are thought to be active. In a genome-wide screen of paediatric and adult glioma cells, we identified a co-ordinated upregulation of HOX gene expression in the MGMT-independent cell line KNS42. As a recent study has proposed a mechanism for this observation whereby transcriptional activation of the HOXA cluster is reversible by a PI3-kinase inhibitor through an epigenetic mechanism involving histone H3K27 trimethylation, we sought to investigate whether this was active in our system. We thus treated KNS42 cells for 24 hours with the dual PI3-kinase / mTOR inhibitor PI-103 at 5x IC50 and carried out gene expression profiling using Illumina HT-12 microarrays.
2011-01-08 | E-TABM-890 | biostudies-arrayexpress
Project description:Temozolomide (TMZ) resistance of glioma cells is currently a critical problem in glioma clinical treatment. In this study, we reveal a bivalent function of a super-enhancer RNA LINC02454 in modulating glioma cell sensitivity to TMZ via regulation of SORBS2 and DDR expression. LINC02454 increased TMZ sensitivity by maintaining 3D chromatin structure and promoting SORBS2 expression, but paradoxically decreased TMZ sensitivity by binding to the DDR1 locus and promoting DDR1 transcription. This study proposes a new regulatory mechanism governing glioma cell sensitivity to TMZ and provides new insights that may improve therapies against glioma.
2024-01-10 | GSE229600 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below. BACKGROUND: Gliomas evade current therapies through primary and acquired resistance and the effect of temozolomide is mainly restricted to the subgroup of methylguanin-O6-methyltransferase promoter (MGMT) hypermethylated tumors. Further resistance markers and pathways against chemotherapy and radiotherapy are largely unknown and would help for better stratification. METHODS: The diagnostic cohorts involved clinical data and methylation profiles of the NOA-08 (n = 104, elderly glioblastoma) and the EORTC 26101 (n = 297, glioblastoma) studies and 398 patients with glioblastoma from the Heidelberg center. Twenty-eight glioblastoma CpGs from 17 DNA damage response (DDR) genes that negatively correlate with expression derived from a 450 DDR gene list as well as telomerase reverse transcriptase (TERT) promoter mutations were investigated for outcome and interaction with therapy and classifier assignments. RESULTS: CpG methylation in IDH wildtype tumors had the highest association with the mesenchymal (MES) and receptor tyrosine kinase (RTK) I glioblastoma subgroup. MES tumors have lower tumor purity and differ in copy number variations on chromosomes 7 and 10 from the RTK I and II subtypes. CpG hypomethylation of DDR genes (TP73, CCND3, CSNK1E, EXO1, CUL4A and PRPF19) correlated with worse patient survival in particular in MGMT unmethylated tumors. TERT promoter mutation is most frequent in RTK I and II subtypes and associated with worse survival in primary glioblastoma. Primary glioma cells show methylation pattern that resemble RTK I and II glioma and differ from long term established cell lines. Knock-down of selected resistance genes PRPF19 and TERT increase sensitivity to temozolomide treatment in vitro. CONCLUSION: Methylation of DDR genes and TERT promoter mutations are associated with tumor prognosis, dependent on the methylation cluster and MGMT promoter methylation status in high-grade glioma.
2020-11-18 | GSE143843 | GEO
Project description:The acquisition of temozolomide resistance is a major clinical challenge for glioblastoma treatment. Chemoresistance in glioblastoma is largely attributed to repair of temozolomide-induced DNA lesions by MGMT. However, many MGMT-negative glioblastomas are still resistant to temozolomide, and the underlying molecular mechanisms remain unclear. We found that DHC2 was highly expressed in MGMT-negative recurrent glioblastoma specimens and its expression strongly correlated to poor progression-free survival in MGMT-negative glioblastoma patients. In vivo and in vitro, silencing DHC2 enhanced temozolomide-induced DNA damage and significantly improved the efficiency of temozolomide treatment in MGMT-negative glioblastoma cells. It is known DHC2 is related to intracellular cargo transportation. To identify the potential interacted “cargo” DHC2 transported and explore the underlying molecular mechanisms of DHC2-midiated DNA damage repair, we performed subcellular proteomic and bioinformatic analyses.
2022-02-28 | PXD012032 | Pride
Project description:Temozolomide (TMZ) is a frequently used chemotherapy for glioma; however, chemoresistance is a major problem limiting its effectiveness. Thus knowledge of mechanisms underlying this outcome could improve patient prognosis. Here, we report that deletion of a regulatory element in the HOTAIR locus increases glioma cell sensitivity to TMZ and alters transcription of multiple genes. Analysis of a combination of RNA-seq, Capture HiC and patient survival data suggests that CALCOCO1 and ZC3H10 are target genes repressed by the HOTAIR regulatory element and that both function in regulating glioma cell sensitivity to TMZ. Rescue experiments and TAD analysis based on HiC data confirmed this hypothesis. We propose a new regulatory mechanism governing glioma cell TMZ sensitivity.
2019-01-25 | GSE125629 | GEO
Project description:Long-range activation is an essential property of enhancers, yet the features determining long-range enhancer activities have not been systematically investigated due to a lack of high-throughput methods to measure long-range enhancer activities efficiently. To address this gap, we present a long-range massively parallel reporter assay (long-range MPRA), a genome-integrated assay allowing the measurement of hundreds of enhancers at multiple distances away from a promoter in parallel. The long-range MPRA assay features two independent landing pads, which allow for modular control over the genome-integrated promoter and enhancer libraries. We showcased the capability of long-range MPRA by testing over 300 K562 enhancers, as well as a set of enhancer combinations, at distances up to 100kb. We found that enhancers’ long-range activities are primarily determined by their intrinsic strength, with strong enhancers retaining more activity over long distances, while weak enhancers rapidly lose activity. Additionally, we found that GATA1-bound enhancers are more resistant to distance-dependent loss of activity, suggesting that TF binding also modulates long-range function. Finally, testing long-range enhancer activities with three different promoters (HBE, HBG and GAPDH) revealed that long-range E-P interactions rely on not only enhancer properties but also promoter responsiveness.
2025-04-15 | GSE294367 | GEO